Method of producing chroman compounds



Patented June 10, 1947 UN IT ED STATES :1 PATENT OFFICE 2 4211512 METHGD.or rrtoDUciNG CHROMAN coMPo Nos Lee ilrvin Smith aiiilfierbcrtEeUiighadegMinhe apolis, Minn, assig'nors to Regents of the Universityof Minnesota, Minneapolis, Minn.,1a corporation of Minnesota No Drawing.

Continuation of application Serial This invention relatesto neworganiccheinical compositions andtc methods for producing the same. Moreparticularly this invention "re- .aciaims. (c1. 260M333) lates to cyclicether compositions of the cou'- marane and chromane classesand tomixtures of materials including such c'cmpositionsand to methods ofproducing such compositions and mixtures from available and relativelyeconom ical ingredientsnotablyhydroquinone compounds and allylichalides.

We have discovered that when a hydroqui= nonecompoun'd having vacant atleast one position ortho to'the hydroxy "group is reacted-with anallylic halide; reactions take place producing the newcompositions andmixturesofthe present invention. Thus, whenhydroquinone compounds suchas substituted hydroquinones, laydroquinone others, hydroquinone estersor hydroquinone derivatives, having "vacant at'least one positionorthoto an'hydroxy group arereacted with an allylic halide compound,desirably an allylic chloride, a reaction "or combination takes placeyielding the new and useful compositions and mixtures. The,hydro'quinone :compound contemplated 'herein'may also be .de'sig natedas alkyhstibstituted-patra-di-hyclroxybenzenes, and their mono-ethersand monoesters.

It is,therefore, an object of the present invention to provide theaforementioned "methods of producing the described compositions andmixtures and to provide such compositions and mixtures.

More specifically, it is an object of the invention to provide a methodof reacting hydroquinone compounds, and an allylie chloride and thecompositions resulting from such method.

It is also an object of the invention to utilize any exhibited effect ofthe herein described processes and/or products and to utilize such.processes and/or products .in any of their. known or hereinafterdiscovered capacities.

Other and further objects are those inherent in and implied by theprocesses and products hereinafter described and claimed.

The methods of the present invention may be stated generally acomprising the reaction of chlorides andbromides either with or withoutcatalysts.

The "substituted hydroquinone compounds: may be compounds such asthealkyl subst'ituted hydrcqui-nones bearing: one, two or threesubstitution "groups which may be the "same or different radicals.Thahydroquinone derivatives contemplated for use in the presentinvention may be hydroquinone ethers :sueli'as the methyl, ethyl,propyl, allyl cyclohexylcr hydroquinone esters such as theacetates,propionates, benzoates and the like.

The process may i be carriedcut without ta solvent or in the resenceofas'clvent suchvasben zene, petroleumvether, glacial acetic acid,decahydronaphthalene andthe like. The reaction may be carried out in aninert atmosphere, or in a reaction vessel from which air has beenremoved, and may be :carried out-at atmospheric or super atmosphericpressures.

The ally-lie "halide compounds utilized in the present inventiomhave thegeneral structural formula .RI XCHCH=C/ it B: where is a halogen and R,R and R are either hydrogen atoms or alkylradicals, andincludesubstances such as *allyl chloride, famesyl bromide, .farnesyl chloride,geranyl bromide, geranyl chloride, 1-chlor-phytene-2, ally bromide,crotyl chloride, crotyl bro-mide, .l-bromphytene-2 and similaranyiicinaudeccmpcunus having the structure given.

Accordingto the method of the present invention, the hydroquinonecompound ingredient is reacted with the allylic halide under suitableconditions, usually with heat and sometimes under pressure. After asuitable reaction period the resulting compositions are separated andthen purified.

The methods are illustrated by the following specific examples whichmust, however, not be construed as limiting the scope of the inventionherein claimed.

Example I An example of the principal process of the invention is thereaction between trimethyl hydroquinone and the simplest allylic bromidewhich is allyl bromide.

A mixture :of iOl- .-.grfani ofmtri-methyl "hydroquinone (sometimes aspseudocumonydro quinone) and 01-1 68; of'iallylr lcrornidewhich: is 2aliquid and: henceaictsras; asolvent tor: the crysta'llinetriiiithtyl.hydrodttinone, is heated in a sealed'tubexat C. .Aafterfkfivehours'rofheating, the tube istcooldiaar-rd opened; ethyl sether is addedand 'acts asma solvent *ior the-resultant reaction mass.Atterifiltration the, etheris-evamorate'd'; crystalline residue: at:Mlesram, representing the first extraction only, resulted. The

hydrobromic acid which is also produced as a product of the reaction andwhich establishes a pressure in the reactiontube is vaporized with theethyl ether.

In this reaction an amount of allyl bromide was used which is in excessof the stoichiometric equivalent, based upon the trimethyl hydroquinonepresent. This is desirable in order to use all of the crystallinetrimethyl hydroquinone, which would otherwise remain and contaminate theresultant end product.

The equation of the reaction and structure of the end product aresubmitted to be as follows:

The resulting product being a 2-2- disubstituted 6 hydroxy chromane.

The reaction of trimethylhydroquinone with gamma-gamma dimethyl allylbromide is an example of this type of reaction. When one gram oftrimethyl hydroquinone is heated with about three grams of crudegamma-gamma dimethyl allyl bromide in a sealed tube at 140 C. a reactionensues. I-Iydrobromic acid results as one of the products of thereaction, and as in Example I, produces a pressure in the sealed tube.When the reaction has proceeded for four hours, the tube is cooled andopened and the mixture is ex- 7 A, izijj tracted with ethyl ether whichserves to dissolve the principal resultant ingredient. The ether solventis then evaporated and the residue recrystallized from dilute aqueousethyl alcohol. The crude first crop yield according to this procedurewas 0.7 gram of white crystalline material having a melting point of89-90 C. The product in this instance is 2,2,5,7,8 pentamethyl 6 hydroxychroman. When the product made in accordance with example was fed toproperly conditioned female test rats, it was found to exhibit vitamin Eactivity in single mg. doses.

Example III When l-brom-phytene-Z is used as the gammagammadisubstituted allylic halide the reaction proceeds as illustratedgenerically in Example II.

Thus when 5 grams of crude l-brom-phytene-Z and 2 grams of trimethylhydroquinone are heated in a sealed tube at C. a reaction takes placewhich after four hours yields a dark liquid mass. Hydrobromic acid whichis developed during the reaction establishes a pressure in the sealedreaction tube, as in the reactions set forth in Examples I and II. Thereaction tube is cooled and opened after four hours of heating and themixture is dissolved in ethyl ether and filtered. The ether solution isthen thoroughly washed by shaking with water. The washing serves toremove the hydrobromic acid, and is repeated until the wash water is nolonger acid to litmus. The ether solution is then dried over sodiumsulphate and after drying the ether is evaporated. The residue, which isa dark brown liquid, is then distilled. The boiling point, in a vacuumof 1 10 millimeters of mercury as determined with a thermometer in theliquid, was about C. The final product of the foregoing process is athick, viscous, pale-yellow liquid. It is sensitive to air, oxidizing toa dark brown liquid, and it is therefore necessary to keep it in aninert atmosphere such as nitrogen, or in a sealed evacuated container.

The amount of 1-brom-phytene-2 used in the described reaction isslightly in excess of the stoichiometrically equivalent amount, basedupon the amount of trimethyl hydroquinone present.

The reaction and structure of the resultant product can probably berepresented by the following reaction:

The product produced in accordance with the present example is a paleyellow fairly viscous oil and when biologically assayed for its vitaminE activity was found to be 100% active in 3 mg. doses. That is to say,when the product of this example was fed in single 3 mg. doses tostandardized conditioned female test rats, litters of live young wereproduced in 100% of all rats fed, and the activity of the product wasequal, 5 weight for weight, to natural alpha toco-pherol.

irbyever, the prdduct of" the present example is not identical namraialpha tocophei-ol since the former is racemic (non-rotatory) abeiit thenumber two carbon atom, while the Iatteris rotatory "ab 't'thesa-me; Thenew product oi this-proce e ma thus, with reason as racemicahatocopherc'l.

Example rv l mixture of "2 grams meta xylohydrequinone and "6.5 gramsl-bror'n phytene-2 was heated in a sealed tube at 120 C. for 3' hours;The crude product was extracted with ethyl ether and unreacted"hydroquinon e was washed out with 1% aqueous potassiumhydroxidesolution. The ether layer" was then washedwith water and dried oversodium sulphate. The ethyl ether was then distilled offend the residuedistilled. in a molecular still, boiling taking place at'l20-l30 C. at1X m'fn. "pressure, the boiling temperature being taken withnthe'thermometer in the liquid The thus distilled product was a pale yellowoil, gave a positive "phenol test thus showing the presence' of a freehydroxyl group, reduced silver nitrate in methanol.

The product when fed to properly conditioned female test rats evidencedvitamin E activity in single 20 mgpdoses: in of all animals fed.

Example V Agmixtureof 2- grams para kylohydroquinone andfi grams l-bromphytene-2 was heated in a sealed tube at 1509C. for 5 hours. The crudeproduct was purified inthe manner set forth in Example IV. The productboiled at -150" C. in the molecular still, was light yellow in color,very viscous, and wasbelieved to be a mixture,

. Example VI As an example of the use of a reaction catalyst, 0.1 grain.of trimethyl hydroquinone in'ay be reacted with 01cc. allyl momma in thepresence f several percent Ofziric chltiri'de. The reaction mixtureisheated to 110 C. in asealed' tube for five'hours. The resultant productwhich is somewhat lessfpure than that, inEX'ample I is eX-- tracted withethyl ether and purified as in Example I. e

'As a further example or the manner in which the reaction is carried outwith the Xylohydroquinone compounds the following. is given.

Example VII aprobabl structdral r together with the rmonoal-lylationproduct; i

OHa- -'O'He I no i r In the foregoingeizaifipka the a l lylhalides-usedWe're the bromides, but other halid her in which theinvention may becarried :out with other halides, particularly the chlorides; "thefOlIOWlng is given: e e H Em-ample VIII A mixture of 1 gram trimethylhydroquinone, and 5 cc. allyl chloride was sealed in a Carius tube. Thetube was then hated to I50 (7. for three hours and upon open-ing o'ftheti' be, la coiisiderable quantity of hydrogen chloride gasescaped. Theresultant reaction ,r'nixtiire wasdi "ssolved in ethyl ether and theether sdldtio'h steam distilled. 600 mg-..o f"a' crystalline productWeisfih tered from the distillate and was furthenp ri byrecrystallization from petroleum ether The thuspurified pro'duct h ad amelting palm; of 1305-131" (3. and is tenevea. to be 2, 45s,"T-tetramethyl-5 hydroxy cournarane, has the following formula: i

GHr a trample-1X mixture of l g ramtrimethyl hydrequi-none and '4 cc. of-purecrotylchloride was sealed ina Garius 'tubeand heated to C. for fodrhours.

The product wasdiso-lved out with ethyl ether. A crystallineprcductremained: after evaporation of the ether. "The crystallizedjproduct wasfurther purified by recrystallization from petroleum ether, the yieldbeing approximately 40 0* mg. ar.-

ter further pdrification by recrystallization from petroleum ether thecrystalline product had a meltingpdi nt of 117-1173 Cgaridls believed toconsist predominately of 2,3,45,7-petitarimthYl-5 hydro'iiy couma'rane.e

If desired, any'of the foregoingreactions may be carried out atatrhcsphe pressure providing the reaction mixtureds protected: bya noiioxidizihg atmosphere. These examples also. 111w trade theuse ofcatalysts are seivnts for the reacting ingredients. iAs'examples of"suichproceduresthe :followihg are given:

Example nears.

emaileu withe'qual facility. As an example of the inan fled chloride wasevolved. The'reacti'on mixture was then cooled and ethyl ether added.The solution was then washed with water and then with a dilute aqueoussolution of sodium hydroxide and then again with water. The dry solutionwas concentrated on a steam bath and then permitted to cool. Uponcooling, a crystalline substance precipitated, the first crop being 700mg. having a melting point of 115-416 C. andthe second crop being 1.1grams having a melting point of 104-105.5 C. The product probablyconsists predominantly of 2,3,4,6,7 pentamethyl -hydroXy coumaran, andwhen fed to properly conditioned female test rats exhibit a vitamin Eactivity in single 50 mg. doses.

Many of the products especially the liquid ones, prepared in accordancewith the present invention are readily oxidized and oxidation and lossof effectiveness of resultant products may be re sisted by conversion ofthe product to esters. Thus, the acetates, benzoates, palmitates, andthe like esters may be prepared. As an example of such procedure thefollowing is given:

Example XI The product resulting from the reaction of trimethylhydroquin-one and crotyl chloride prepared in accordancewith Example IXhereof was acetylatedby boiling With an excess of acetic anhydride. bydilution with water and the crystalline product filtered off. Themelting point of the acetate compound was 70.5+71 C. I

Catalysts may be used in any of the foregoing procedures, zinc chloride;aluminum chloride, mercuric chloride being preferred.

In any of the foregoing procedures a hydroquinone compound having atleast one position vacant ortho to the hydroxy group, and where thisphraseology is used in the specification and claims it is intended tocover the alkyl substituted compounds such as the methyl, ethyl, propyl,amyl or the like alkyl substituted hydroquinones, the monoethers such asthe methyl, ethyl, propyl, allyl, cyclohexyl or the like monoethers, andthe monoesters, such as acetates, propionates, benzoates or the like.Where the ether or ester type of compounds are used, the substituentether and ester groups may be left in the finished product or cleaved asdesired. As to the allyl halide, it is preferable to use the bromides,or the less expensive and equally efiective chlorides. The iodides areless efiicacious since the reaction is adversely affected by thehydriodic acid evolved. Products made by the foregoing procedures areactive anti-oxidants when a free hydroxyl group is present, and areuseful for the purposes to which such compounds have heretofore beenutilized. The esters of the resultant products are more stable than theunesterified products and the esters, for example, the acetates, areuseful where oxidation is to be resisted. I

In general the absorption curves closely parallel the absorption curvesof tocopherols derived from natural sources and indicate that thecompounds of thisv invention may be identified with the natural productsand are similarly useful. The term tocopherol was introduced in .theliterature by Evans, Emerson and Emerson, Journal of BiologicalChemistry, vol. 113, p. 321 (1936), and refers to naturally Occurringsubstances having biological (vitamin E) activity.

The present application is a continuation of application Serial No.211,078, filed May 31, 1938. It is obvious that many variations may bemade The resultant acetate was precipitated in the procedures herein setforth Without departing from thespirit of the inventiondescribedandsubstituted allylic halide having a double bond in thebeta-gamma position with an aromatic compound containing a free hydroxylgroup and an unsubstituted position ortho to said hydroxyl group andselected from :the group consisting ofalkyl-substituted-para-di-hydroxy-benaenes, and their mono ethers andmono esters, in the presence of an acidic substance. 7

2. A process for producing chromans which comprises heating agamma-gamma-dialkyl-substituted allylic halide having a double bond inthe beta-gamma position with an aromatic compound containing a freehydroxyl group and an unsubstituted position ortho to said hydroxylgroup and selected from the group-consistingofalkyl-substituted-para-di-hydroXy-benzenes and their monoethers and monoesters, in the presence of a non-oxidizing gas, and in the presence ofanadded acidic substance. 7

3. A process for producing chromans which comprises heating aamma-gamma-dialkyl-substituted allylic halide having a double bond inthe beta-gamma position with an aromatic compound containing a freehydroxyl group and an unsubstituted position ortho to said hydroxylgroup and selected from the group consisting ofalkyl-substituted-p-ara-di-hydroxy-benzenes and. their mono ethers andmono esters, and a solvent, in the presence of an acidic catalyst.

4. A process for'producing chromans which comprises heating agamma-gamma-dialkyl-substituted allylic halide havinga double bond inthe beta-gamma position with an aromatic compound containing a freehydroxyl group and an unsubstituted position ortho to said hydroxylgroup and selected from the group consisting ofalkyl-substituted-para-di-hydroxy-benzenes and their mono ethers andmono esters, in a sealed vessel.

5. A process for the production of chromans which comprises reactingtrimethyl hydroquinone and a gamma-gamma-di-alkyl-substituted allylichalide having a double bond in the beta-gamma position, in the presenceof an acidic substance.

6. A process for producing chroman compounds comprising reacting agamma-gamma-di-alkyl substituted allylic halide having a double'bond inthe beta gamma. position with an alkyl-substituted para-di-hydroxybenzene having an unsubstituted position ortho to a under acidicconditions. p

7. The process of claim 6 and in which an added acidic substanceisemployed.

8. The process of claim 6 and in chloride is employed' LEE IRVIN SMITH.

HERBERT E. UNGNADE. REFERENCES CITED The following references are ofrecord in the file of this patent:

FOREIGN PATENTS which zinc Date 279,864 Germany 1914;

(References on following page) hydroxy group,

9 Number Country Date 374,142 Germany 1923 394,7 9'? Germany 1924 OTHERREFERENCES Karrer, Helv. Chemica Acta, 21, pages 520- 25 (1938), alsopages 309-13, 820-25, 1234-40, 1756-59.

Smith, Journal Amer. Chem. Soc, 55, pages 4151-3.

10 Hahn, Chemical Abstracts, 23, pages 2705-6. Ferholz, Journal ofAmerican Chem. $00., 60, March, 1938, pages 700-05.

Evans et al., Journal of Biological Chemistry, 5 vol. 113 (1936), pages321-332.

Olcott et 2.1., Journal of Biological Chemistry, vol. 104 (1934) pages423-425.

Karrer, Organic Chemistry, trans by Mee, 1 Nordman Pub. 00., New York,1938, pages 87-96,

